JP2012519180A - Peptidomimetic cyclic compounds for treating retinitis pigmentosa - Google Patents

Abstract

The present invention relates to methods for treating retinitis pigmentosa using β-turn peptidomimetic cyclic compounds, or derivatives thereof. A β-turn peptidomimetic cyclic compound can be used alone and in combination with and / or in combination with one or more other compounds, molecules or drugs useful for treating retinitis pigmentosa.

Description

  This application claims the benefit of US Provisional Application No. 61 / 208,806, filed February 27, 2009. All of the teachings of the above applications are incorporated herein by reference.

  Retinitis pigmentosa is a group of inherited diseases in which abnormalities in photoreceptor cells (rods or cones) or retinal pigment epithelium of the retina lead to progressive blindness. Some forms of retinitis pigmentosa are dominant, requiring only one gene from either parent, others are X-linked, requiring only one gene from the mother. Some humans are mostly male, but hereditary hearing loss also develops.

  The retinal pigment epithelium provides nutrients and support for retinal photoreceptors, in particular inhibitors of oxidative stress and apoptosis. For example, neurotrophins in the retinal pigment epithelium activate anti-inflammatory and antioxidant factor release.

  In retinitis pigmentosa, chronic death of retinal photoreceptors (rods and cones) occurs. These visual cells are involved in visual acuity at low light intensity, but since this gradually degenerates, visual acuity in the dark is deteriorated. Early symptoms of retinitis pigmentosa often begin early in childhood. Over time, progressive peripheral vision loss occurs. In later stages of the disease, humans have a small central vision and a small peripheral vision (tunnel vision). There is a need in the art for a method of treating retinitis pigmentosa.

The present invention provides a method of treating retinitis pigmentosa in a subject in need of treatment comprising administering to the subject an effective amount of a β-turn peptidomimetic cyclic compound. In one embodiment, the β-turn peptidomimetic cyclic compound comprises a macrocyclic ring of 13 to 17 carbon atoms. In a more specific embodiment, the β-turn peptidomimetic cyclic compound is represented by Structural Formula (I):
Wherein R ¹ and R ³ are independently selected from hydrogen, C ₁ -C ₆ alkyl, aryl, or amino acid side chain substituents found in the 20 protein-amino acids in any enantiomeric configuration; R ² and R ⁴ are independently hydrogen or C ₁ -C ₆ alkyl; or R ¹ and R ² together with the carbon atoms attached to them form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; Or R ³ and R ⁴ together with the carbon atom bonded to them form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; R ⁵ and R ⁶ are hydrogen or C ₁ -C ₆ alkyl; Y is hydrogen or 1 or 2 aromatic substituents; X is O, N, S, P, Se, C, 1-6 charcoal Alkylene atom, SO, selected from SO ₂ or NH; n is an 1, 2, 3, 4 or 5; second compound of formula (I) by reaction of the linker is a homobifunctional compound It is an effective linking group for forming a monomer. _Suitable linker groups, NH 2, OH, SH, COOH, CH 3 CO, CHO, and _NH-CH 2 -COOH include, but are not limited to.

In another embodiment of the invention, X is O, S or NH, R ¹ , R ³ , R ⁵ and R ⁶ are each a hydrogen atom and the macrocyclic ring has 14, 15 or 16 ring atoms. Have.

In another embodiment, R ¹ and R ³ are derived from a series of different proteogenic amino acid side chains.

  In another embodiment of the invention, X is O, S or NH.

In certain embodiments, the β-turn peptidomimetic cyclic compound of Formula I is represented by the following formula: or a pharmaceutically acceptable salt thereof.

The compound is referred to herein as D3. D3 has been demonstrated to have Trk modulator activity.

In another embodiment, the β-turn cyclic compound is selected from the group consisting of compounds represented by the following formula, or any pharmaceutically acceptable salt thereof.













and

These compounds can have Trk modulator activity.

In one embodiment, the present invention provides an effective amount of a structural formula (D3):

To a method of treating retinitis pigmentosa in a subject in need of treatment, comprising administering a β-turn peptidomimetic cyclic compound represented by: or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides the subject with an effective amount of Formula 3Aa:

To a method of treating retinitis pigmentosa in a subject in need of treatment, comprising administering a β-turn peptidomimetic cyclic compound represented by: or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention provides the subject with an effective amount of Formula 3Ak:

To a method of treating retinitis pigmentosa in a subject in need of treatment, comprising administering a β-turn peptidomimetic cyclic compound represented by: or a pharmaceutically acceptable salt thereof.

  The invention further relates to the use of a compound described herein (eg, a β-turn peptidomimetic cyclic compound) for the manufacture of a medicament for treating retinitis pigmentosa in a subject in need of treatment.

  The invention further relates to a pharmaceutical composition useful for treating retinitis pigmentosa in a subject in need of treatment. The pharmaceutical composition comprises a compound described herein (eg, a β-turn peptidomimetic cyclic compound) and a pharmaceutically acceptable carrier.

  The foregoing will become apparent from the following more specific description of exemplary embodiments of the invention as illustrated in the accompanying drawings. In the drawings, like reference characters designate the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon describing embodiments of the invention.

  In the drawings and description of support experiments, the compound ID includes the prefix MIM. A compound ID with a prefix is the same as a compound ID without a prefix. For example, MIM-D3 and D3 represent the same compound.

Code for β-turn backbones numbered 1, 2, and 3 for Trk modulator compounds. FIG. 3 is a code for an X-substituent in the backbone, marked A, B, C and D, for a Trk modulator compound. Code for backbone dipeptide R ¹ and R ² substituents for Trk modulator compounds. The full letter codes for β-turn peptidomimetic cyclic compounds containing the backbone (1, 2 or 3), X-substituent (A, B, C or D) and dipeptide amino acids (R ¹ and R ² ) are shown.

  The present invention relates to a method of treating retinitis pigmentosa in a subject in need of treatment comprising administering to the subject a β-turn peptidomimetic cyclic compound. As used herein, a “β-turn peptidomimetic cyclic compound” refers to a cyclic compound that mimics the β-turn region of a neurotrophin receptor ligand (eg, NGF, NT-3, NT-4 and BDNF). In certain embodiments, the β-turn peptidomimetic cyclic compounds of the invention can be neurotrophin tyrosine kinase (Trk) receptor modulators. In another specific embodiment, the β-turn peptidomimetic cyclic compound can be a p75 receptor modulator. In yet another embodiment, the β-turn peptidomimetic cyclic compound can be both a p75 receptor modulator and a Trk receptor modulator.

  In one embodiment, the β-turn peptidomimetic cyclic compound is represented by Structural Formula I. In certain embodiments, the β-turn peptidomimetic cyclic compound is Compound D3 or a derivative of Compound D3.

  In another embodiment, the β-turn peptidomimetic cyclic compound is a compound selected from the group consisting of 1Ad, 3Aa, 3Ak, 3Ba, 3Bg, 3Bi, 3Ca, 3Ce, 3Ck, 1Aa, 1Ba, 3Ac and 3Ae. It can be.

  Although the β-turn peptidomimetic cyclic compounds of the present invention can be Trk receptor modulator compounds or p75 receptor modulators, the usefulness of β-turn peptidomimetic cyclic compounds in the treatment of retinitis pigmentosa Or its modulation may depend on other activities such as modulation of any other receptor useful in the treatment of retinitis pigmentosa.

  As used herein, a “Trk receptor modulator compound” is a compound that is a TrkA receptor agonist, a TrkC receptor agonist, or both a TrkA receptor agonist and a TrkC receptor agonist.

  As used herein, “modulate” or “modulator” refers to stimulating or antagonizing a receptor.

  As used herein, a “p75 receptor modulator” is a p75 receptor agonist or antagonist.

<Neurotrophin and neurotrophin receptor>
Neurotrophin (NTF) is a dimeric protein family that controls neuronal proliferation, survival and differentiation in all vertebrate species. NTF includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4). These NTFs bind to two transmembrane receptors, the high affinity receptor family tyrosine kinase (Trk) (TrkA, TrkB and TrkC) (K _d = 10-100 pM) and the p75 receptor (K _d = 1 nM). . Trk family receptor ligands are fairly selective (eg, NGF binds to TrkA, BDNF binds to TrkB, and NT-3 binds primarily to TrkC).

  Neurotrophins and their receptors have been identified in conjunctival goblet cells (CGCs) (Rios, JD, et al., “Role of Neurotrophins and Neurotrophin Receptors in Rat Conjunctive Goblet Cells”). Visual Science, 48: 1543-1551 (2007)) CGC is a major source of large amounts of soluble mucin in the tear film, these mucins from the exogenous agent (bacterial or chemical) to the cornea and conjunctiva It provides a physical and chemical barrier that protects the surface and facilitates the creation of the smooth refractive surface necessary for clear vision.

<Β-Turn Peptidomimetic Cyclic Compound>
In one embodiment, the β-turn peptidomimetic cyclic compound comprises a macrocyclic ring of 13 to 17 carbon atoms. In a more characteristic embodiment, the β-turn peptidomimetic cyclic compound is represented by Structural Formula (I):
In which R ¹ and R ³ are independently selected from hydrogen, C ₁ -C ₆ alkyl, aryl or amino acid side chain substituents found in the 20 protein-amino acids in either enantiomeric configuration; R ² And R ⁴ are independently hydrogen or C ₁ -C ₆ alkyl; or R ¹ and R ² together with the carbon atom attached to them form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; or R ³ and R ⁴ together with the carbon atom bonded to them form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; R ⁵ and R ⁶ are hydrogen or C ₁ -C ₆ alkyl; Y is hydrogen or one Or two aromatic substituents; X is O, N, S, P, Se, C, 1-6 carbon atoms Is selected alkylene child, SO, from SO ₂ or NH; n is an 1, 2, 3, 4 or 5; LINKER the secondary amount of a compound of formula (I) by reaction with a homo bifunctional compound An effective linking group to form a body. _Suitable LINKER groups, NH 2, OH, SH, COOH, CH 3 CO, CHO, and _NH-CH 2 -COOH include, but are not limited to.

The 20 amino acid side chain substituents include alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and Examples include the tyrosine side chain. For example, the side chain of glutamic acid is
It is.

In another embodiment of the invention, X is O, S or NH, R ¹ , R ³ , R ⁵ and R ⁶ are each a hydrogen atom and the macrocyclic ring is 14, 15 or 16 ring atoms. Have

In another embodiment, R ¹ and R ³ are derived from a series of different protein amino acid side chains.

  In another embodiment of the invention, X is O, S or NH.

In certain embodiments, the β-turn peptidomimetic cyclic compound is D3 (Mariatchuk et al, Mol Pharmcol 57 (2): 385-391, 2000 (incorporated herein by reference in its entirety) and US 6,881. 719 (see incorporated herein by reference in its entirety), or a derivative of D3. Many derivatives of D3 and other compounds of formula I are envisioned for use in the methods of the present invention, simple modifications, such as biotinylated forms, and molecules in which two units are linked by a dimer including. Other compounds of other D3 derivatives and the formula I are 20 proteins - including side chain R ¹ to R ⁶ having the amino acid side chain substituents found in amino acids.

  Side chains typical for protein amino acids (eg, Arg, Trp, His) allow the formation / design of various structures that are easily generated D3 derivatives and other compounds of formula I, and many types of Functional groups can be included.

One or more substituents Y may be hydrogen or one or two aromatic substituents such as nitro, amino, halo, alkyl, such as alkyl of 1 to 6, preferably 1 to 4 carbon atoms, It may be aryl, such as phenyl or naphthyl. The alkyl and aryl substituents Y may be unsubstituted or substituted, with suitable substituents being nitro and alkyl of 1 to 6 carbon atoms. Y may also be derivatized with a functional group such as biotin. The X group may be any nucleophilic atom such as O, N, S, P, Se, but may be other such as C, or typically 1-6 carbon atoms. Or an alkylene radical such as methylene; SO, SO ₂ or NH. The point of attachment can be ortho- or meta-to benzoylcarbonyl. Acceptable values for “n” are 0, 1, 2, 3, 4, and 5. The linking side chain incorporating X is an aliphatic represented by structure (I).

The side chain alkyl groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ can be varied in many ways to enhance the biological activity of these compounds. Typically, R ¹ , R ² , R ³ , and R ⁴ are amino acid side chain substituents found in the 20 protein-amino acids, eg, glutamic acid, lysine, ornithine and threonine in any enantiomeric configuration. Side chain. When the R ¹ substituent is an amino acid side chain, the other substituent on that carbon, R ^2, is typically hydrogen, but may be methyl, ethyl or benzyl. R ¹ and R ² can also be taken together with their intervening atoms to provide cyclopropane, cyclobutane, cyclopentane, and cyclohexane residues. R ³ and R ⁴ are related in the same way as R ¹ and R ² as described above. That is, one of them is an amino acid side chain and the other of these two groups is most often hydrogen, but methyl, ethyl, propyl or benzyl could also be possible. In addition, R ³ and R ⁴ can be taken together with intervening atoms to provide cyclopropane, cyclobutane, cyclopentane, and cyclohexane residues.

The range of variations of R ⁵ and R ⁶ is much more extensive, and the most common substituent at these positions is hydrogen or methyl. These substituents can also be designed to correspond to one of the 20 protein-amino acid side chains, in particular methyl.

Side chains that have been found to contribute particularly to biological activity are R ¹ and R ³ as side chains of lysine, glutamic acid, tyrosine, isoleucine, asparagine, and threonine, R ² , R ⁴ , R ⁵ as hydrogen. , And R ⁶ . The one or more side chains are selected to correspond, inter alia, to side chains within the turn region of NGF.

Generally macrocycle has a 13 to 16-membered ring, wherein, X substituent is O, N, is S, SO or SO _2,.

In another embodiment, the β-turn peptidomimetic cyclic compound is selected from the group consisting of 1Ad, 3Aa, 3Ak, 3Ba, 3Bg, 3Bi, 3Ca _, 3Ce, 3Cg, 3Ck, 1Aa, 1Ba, 3Ac and 3Ae.

In yet another embodiment, the β-turn peptidomimetic cyclic compound comprises various substituents (eg, amine, guanidine or methylsulfonamide) (see FIG. IB) as well as dipeptide amino acid fragments (see FIG. 1C). A compound containing a cyclic amino, ether or sulfide backbone (see FIG. 1A) with R ¹ and R ² groups comprising (see also FIG. 1D).

  The compound of the present invention is present in an effective amount. As used herein, the term “effective amount” refers to an amount sufficient to treat (therapeutically or prophylactically) the target disorder when administered on an appropriate dosing schedule. For example, an effective amount reduces or ameliorates the severity, duration or progression of the disorder being treated, prevents the progression of the disorder being treated, causes regression of the disorder being treated, or prevents or treats another therapy Sufficient to enhance or improve the effect.

  In the present specification, “retinal pigment degeneration” is a broad concept, and isher syndrome, Leber's congenital cataract, rod cone disease, Valde-Beedle syndrome, refsum disease, Stargard disease, total choroidal atrophy, brain rotational atrophy Syndrome, Laurence Moon syndrome, Wardenburg syndrome, Alport syndrome, Kearns-Sayer syndrome, abetalipoproteinemia, Hurler syndrome, Schier syndrome, San Philip syndrome, neuronal ceroid lipofuscinosis, Kufs syndrome, Yansky Beershawski It is intended to include, but is not limited to disease, Vogt Spielmeier Batten disease, and muscular dystrophy.

  As used herein, a subject refers to an animal, such as a mammal, and is a primate (eg, human), cow, sheep, goat, horse, pig, dog, cat, rabbit, guinea pig, rat, mouse or other bovine species. , Sheep species, horse species, dog species, cat species, rodent species, or mouse species. In one embodiment, the subject is a human.

  The term “treating” includes both therapeutic and prophylactic treatment (reduces the likelihood of onset). The term reduces, inhibits, reduces, reduces, prevents or stabilizes the onset or progression of a disease (eg, a disease or disorder described herein) and reduces the severity of the disease. Or to improve the symptoms associated with the disease.

  As used herein, the term pharmaceutically acceptable salt refers to a salt of an administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids thereof. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from, for example, aliphatic, aromatic, carboxylic acid and sulfonic acid class organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, camphorsulfonic acid, citric acid, Fumaric acid, gluconic acid, isethionic acid, lactic acid, malic acid, mucinic acid, tartaric acid, p-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furic acid, glutamic acid, benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandel Acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (besylic acid), stearic acid, sulfanilic acid, alginic acid, galacturonic acid and the like.

  The invention further relates to a pharmaceutical composition for use in treating retinitis pigmentosa in a subject in need of treatment. The pharmaceutical composition comprises one or more β-turn peptidomimetic cyclic compounds of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can also include inert ingredients that do not interact with the control / active agent in the composition. Standard pharmaceutical formulation techniques such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA can be used. Suitable pharmaceutical carriers for parenteral administration include sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg / ml benzyl alcohol), phosphate buffered saline, Hank's solution, Ringer lactate, dextrose, ethanol, surfactants such as glycerol, or excipients.

  In further embodiments, the pharmaceutical composition further comprises certain (ie, one or more) additional therapeutic agents. Additional therapeutic agents suitable for use in the methods and pharmaceutical compositions described herein include, for example, vitamin A (eg, vitamin A palmitate), bendazac, NT-501 (Neurotech) and human. It can be postpartum umbilical cord cells, but is not limited thereto.

<Dosage form>
The composition can be formulated for topical ophthalmic use, for example, in the form of a solution, ointment, cream, lotion, ophthalmic ointment, most preferably an eye drop or eye gel, with suitable conventional additions Products, such as preservatives, solvents that aid drug penetration, and softeners in ointments and creams. Such topical formulations may contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions.

  The active compound may also be applied to the eye via a liposome. In addition, the active compound may be injected into the tear film via a pump-catheter system. Another embodiment of the invention is in a continuous or selective release device, such as, but not limited to, a pilocarpine (Ocusert ™) system (such as that used in Alza Corp., Palo Alto, Calif.). Contains active compound contained. As an additional embodiment, the active compound can be contained in a contact lens placed in the eye, carried by the contact lens, or attached to the contact lens. Another embodiment of the invention includes an active compound contained within a swab or sponge that can be applied to the ocular surface. Another embodiment of the invention includes the active compound contained within a liquid spray administered to the ocular surface. Another embodiment of the invention involves direct injection of the active compound into the eye.

  When the pharmaceutical composition of the present invention for treating retinitis pigmentosa is used as eye drops, any dosage form used for eye drops, for example, aqueous eye drops such as aqueous eye drops, aqueous suspensions. It is provided in cloudy eye drops, viscous eye drops and solubilized eye drops, or non-aqueous eye drops such as non-aqueous eye drops and non-aqueous suspension eye drops. Of these, aqueous ophthalmic solutions are preferred.

  When the pharmaceutical composition of the present invention for treating retinitis pigmentosa is prepared as an aqueous ophthalmic solution, various additives usually used in the aqueous ophthalmic solution do not adversely affect the object of the present invention. Can be appropriately blended. Examples of such additives include buffers, isotonic agents, preservatives, solubilizers (stabilizers), pH adjusters, thickeners and chelating agents.

  The buffer may be selected from the group comprising, but not limited to, phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer (eg, sodium acetate) and amino acids.

  Isotonic agents can be selected from the group including, but not limited to, sugars such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin, polyethylene glycol and polypropylene glycol, and salts such as sodium chloride.

  The preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, alkyl paraoxybenzoates such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid and its salts, thimerosal and chlorobutanol But is not limited to them.

  The solubilizer (stabilizer) may be selected from the group comprising cyclodextrin and its derivatives, water soluble polymers such as poly (vinyl pyrrolidone), and surfactants such as polysorbate 80 (trade name: Tween 80). , But not limited to them.

  The pH adjusting agent may be selected from the group comprising but not limited to hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide and ammonium hydroxide.

  The thickening agent may be selected from the group comprising, but not limited to, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose and their salts.

  The chelating agent can be selected from the group including, but not limited to, sodium edetate, sodium citrate and condensed sodium phosphate.

  When the pharmaceutical composition of the present invention for treating retinitis pigmentosa is prepared as an ointment for an eye, a base compound must be present. The ointment base may be selected from the group comprising, but not limited to, purified lanolin, VASELINE®, plastibase, liquid paraffin, and polyethylene glycol.

  The compositions of the present invention can also be formulated for oral administration using pharmaceutically acceptable tableting excipients including lactose, microcrystalline cellulose, corn starch, stearic acid, and the like. . Oral administration can also include liquid compositions formulated in water, glycols, oils, alcohols and the like.

<Co-administration>
Where the method of the invention includes co-administration, the co-administration comprises a first amount of β-turn peptidomimetic cyclic compound or a pharmaceutically acceptable salt thereof, and a second amount of vitamin A (eg, vitamin A administration of at least one agent selected from the group consisting of A palmitate, Vendazac, NT-501 (Neurotech) and human postpartum umbilical cord cells, wherein the first and second amounts are combined And an amount effective to treat retinitis pigmentosa in a subject in need of treatment. Co-administration includes the administration of first and second amounts of co-administration, essentially simultaneously, eg, in a single pharmaceutical composition or in multiple pharmaceutical compositions. Furthermore, co-administration also includes the use of the compounds in sequential administration in either order. Co-administration comprises a first amount of β-turn peptidomimetic cyclic compound or a pharmaceutically acceptable salt thereof, and a second amount of vitamin A (eg, vitamin A palmitate), bendazac, NT- When comprising separate administration of at least one agent selected from the group consisting of 501 (Neurotech) and human postpartum umbilical cord cells, the agent is administered at sufficiently short intervals to obtain the desired therapeutic effect . For example, each dosing interval that provides the desired therapeutic effect can range from a few minutes to a few hours, and the properties of each component of co-administration, such as efficacy, solubility, bioavailability, plasma half-life and kinetic profile, can be determined. It can be determined in consideration.

<Dose>
The effective amount of a β-turn peptidomimetic cyclic compound depends on the patient's age, gender and weight, the patient's current medical condition and the nature of the retinitis pigmentosa being treated. A person skilled in the art will be able to determine the appropriate dose based on these and other factors. For example, when the pharmaceutical composition of the present invention is used as an ophthalmic solution for treating retinitis pigmentosa in a subject in need of treatment, the aqueous eye drop solution contains about an active ingredient of the compound of the present invention. 0.001-2.5 (w / v)%, for example 0.02-2.0 (w / v), for example about 0.03-1.5 (w / v)%, for example about 0.05- It is desirable to include in an amount of 1.0 (w / v)%. As used herein, weight / volume (w / v) means a specific mass (eg, g / ml) of a solute in a specific final volume. When administered, the compounds and compositions of the invention can be administered once a day, or multiple times a day, eg, twice a day, three times a day, and four times a day. In particularly preferred embodiments, the compounds and compositions of the invention can be administered in doses of 1 to 5 drops, such as 1 drop, 2 drops, 3 drops, 4 drops or 5 drops.

  When the pharmaceutical composition of the present invention is used as an ophthalmic ointment, the ophthalmic ointment contains about 0.001 to 2.5 (w / w)% of the active ingredient of the compound of the present invention, for example 0.02-2. 0.0 (w / v), for example about 0.03 to 1.5 (w / v)%, for example about 0.05 to 1.0 (w / v)%. As used herein, weight / weight (w / w) means the weight of the solute in the final weight of the solution, eg, g / g. When administered, the compounds and compositions of the invention can be administered once a day, or multiple times a day, eg, twice a day, three times a day, and four times a day.

  A description of exemplary embodiments of the invention follows.

  The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

  While the invention has been particularly shown and described with reference to exemplary embodiments thereof, those skilled in the art will recognize that various changes in form and detail may be made within the scope of the appended claims. It will be understood that this is possible without departing from the scope.

<Protection of retinal pigment epithelial cells from degeneration caused by oxidative stress>
The purpose of this study was to investigate the pharmacological concept of neurotrophic prevention of oxidative stress-induced retinal pigment epithelial (RPE) cell degeneration. The purpose of this study was to validate a specific compound as a therapy for retinitis pigmentosa.

<Method>
APRE19 cells were cultured in complete medium followed by serum starvation for 8 hours. Apoptosis was then induced by exposure to oxidative stress (TNFα and H ₂ O ₂ ) for 16 hours in the presence or absence of test compounds or controls. Apoptosis was quantified as the ratio of dead cells to total viable cells + dead cells by counting nuclei stained with Hoechst reagent.

  Test agents included nerve growth factor (agonist of TrkA and p75 receptor), neurotrophin-3 (agonist of TrkC and p75 receptor), and compounds D3, 3Ak, 3Ae and 3Aa.

<Result>
Non-stressed cells are fully viable, but oxidative stress caused 94% apoptotic death of APRE19 cells. Protection of stressed APRE19 cells by neurotrophin NGF or NT-3 has been published.

  Compounds D3, 3Ak and 3Ae allow quantitatively unambiguous protection from apoptosis, depending on the dose. Treatment with compounds D3, 3Ak and 3Ae reduces APRE19 cell death (29%, 24% and 16%, respectively, at 25 μM dose).

  Compound 3Aa allows quantitatively unambiguous protection from apoptosis. However, its protection is dose independent and is lower than that seen with compounds D3, 3Ak and 3Ae. Treatment with compound 3Aa at a 25 μM dose is partial protection resulting in 50% APRE19 cell death.

  Compounds D3, 3Ak, 3Ae and 3Aa can protect RPE cells from death. Treatment with compounds D3, 3Ak and 3Ae resulted in less than 30% cell death, while 3Aa resulted in approximately 50% cell death. These compounds represent possible treatments for retinitis pigmentosa.

  Additional experiments in a mouse model of retinal degeneration were performed. Compound 3Aa was administered and ERG (dark and light adaptation) and the number of outer granule layer rows were observed for both control and drug treated animals. The results showed no statistically significant drug effects compared to controls, but positive trends were observed in the data.

  Although the invention has been illustrated and described, particularly with reference to illustrative embodiments thereof, those skilled in the art will recognize that various changes in form and detail may be made within the scope of the appended claims. It will be understood that this is possible without departing from the scope.

Claims (11)

  A method of treating retinitis pigmentosa in a subject in need of treatment comprising administering to the subject an effective amount of a β-turn peptidomimetic cyclic compound.   The method of claim 1, wherein the β-turn peptidomimetic cyclic compound comprises a macrocyclic ring of 13 to 17 carbon atoms. The β-turn peptidomimetic cyclic compound is represented by Structural Formula (I):
Wherein R ¹ and R ³ are independently selected from hydrogen, C ₁ -C ₆ alkyl, aryl or amino acid side chain substituents found in 20 protein-amino acids; R ² and R ⁴ are independently R ¹ and R ² together with the carbon atom bonded to them form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; or R ³ and R ⁴ are carbon bonded to them Forms a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group with the atom; R ⁵ and R ⁶ are hydrogen or C ₁ -C ₆ alkyl; Y is hydrogen or one or two aromatic substituents; X is O, N, S, or P, Se, C, alkylene of 1 to 6 carbon atoms, SO, SO ₂ or NH Is selected; n is 0, 1, 2; is selected from the group _linker consisting of NH 2, OH, SH, COOH , CH 3 CO, CHO, and _NH-CH 2 -COOH The method according to claim 2. The method of claim 3, wherein X is O, S or NH, R ¹ , R ³ , R ⁵ and R ⁶ are each a hydrogen atom and the macrocyclic ring has 14, 15 or 16 ring atoms. . R ¹ and R ³ are derived from a series of different amino acid side chains, The method of claim 3.   6. The method according to claim 5, wherein X is O, S or NH. The method according to claim 1, wherein the β-turn peptidomimetic cyclic compound is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof.

The β-turn peptidomimetic cyclic compound has the formula 1Ad, formula 3Aa, formula 3Ak, formula 3Ba, formula 3Bg, formula 3Bi, formula 3Ca, formula 3Ce, formula 3Cg, formula 3Ck, formula 1Aa, formula 1Ba, formula 3Ac and formula The method according to claim 1, which is selected from the group consisting of a compound represented by 3Ae, or a pharmaceutically acceptable salt thereof.














Treating retinitis pigmentosa in a subject in need of treatment comprising administering to the subject an effective amount of a β-turn peptidomimetic cyclic compound represented by the following formula, or a pharmaceutically acceptable salt thereof: how to.

Treating retinitis pigmentosa in a subject in need of treatment comprising administering to the subject an effective amount of a β-turn peptidomimetic cyclic compound represented by Formula 3Ae, or a pharmaceutically acceptable salt thereof. how to.

Treating retinitis pigmentosa in a subject in need of treatment comprising administering to the subject an effective amount of a β-turn peptidomimetic cyclic compound represented by Formula 3Ak or a pharmaceutically acceptable salt thereof. Method.